The present invention relates to a new piperazine derivative of the general formula (I) or its pharmaceutically acceptable acid addition salt, and process for the preparation thereof. 
wherein R1 and R2 are independently hydrogen, C1-C4 alkyl, C1-C4 alkylcarboxyl, C1-C4 alkylcarbonyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl or C1-C4 hydroxyiminoalkyl, or R1 and R2 are fused to form C3-C4 unsaturated ring;
R3, R4, R5, R6, and R7 are independently hydrogen, halogen, hydroxy, nitro, amino, C1-C4 alkyl, C1-C4 alkylcarboxyl, C1-C4 alkylcarbonyl, C1-C4 alkoxy or C1-C4 thioalkoxy; R8 is C1-C4 alkyl;
Y is oxygen, sulphur, amino, subsitituted amino or C1-C4 thioalkyl;
Z is C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylamino or C1-C4 thioalkoxy;
X1 and X2 are independently CH or nitrogen; and
xe2x80x94Nxe2x95x90Cxe2x80x94 and xe2x80x94Cxe2x95x90Yxe2x80x94 may form a single bond or a double bond provided that if xe2x80x94Nxe2x95x90Cxe2x80x94 forms a single bond, xe2x80x94Cxe2x95x90Yxe2x80x94 forms a double bond, and if xe2x80x94Cxe2x95x90Yxe2x80x94 forms a single bond, xe2x80x94Nxe2x95x90Cxe2x80x94 forms a double bond and R8 is nonexistent.
In the above definitions, C1-C4 alkyl means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
C1-C4 alkylcarboxyl means carboxyl esterified with a lower alkyl such as methylcarboxyl and ethylcarboxyl.
C1-C4 alkylcarbonyl means carbonyl ketonized with a lower alkyl such as methylcarbonyl and ethylcarbonyl.
C1-C4 alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy.
C1-C4 thioalkoxy means methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or tert-butylthio.
C1-C4 aminoalkyl means aminomethyl, aminoethyl, aminopropyl, aminobutyl or the like.
C1-C4 kydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or the like.
C1-C4 hydroxyiminoalkyl means C1-C4 alkyl substituted with hydroxyimino such as hydroxyiminoethyl.
Substituted amino means hydroxyamino, C1-C4 alkylamino, C1-C4 alkoxyamino or the like.
The present inventors had studied for a long time to find compounds having intensive antitumor activity. As a result, now we have finally found out the facts that the present compounds of the general formula (I) and acid addition salts thereof have not only prominent antitumor activities but very low toxicities.
Accordingly, the one object of the present invention is to provide the novel compounds of the general formula (I) and acid addition salts thereof having not only prominent antitumor activities but very low toxicities.
The other object of the present invention is to provide a process for the preparation of the compounds of general formula (I) and acid addition salts thereof.
The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and thus the pharmaceutical compositions can be used to prevent or treat with various kinds of tumors of human beings or mammals.
Therefore, another object of the present invention is to provide pharmaceutical compositions containing the compound of the general formula (I) or an acid addition salt thereof as an active ingredient.
Acids which can be reacted with the compounds of the general formula (I) to form acid addition salts are pharmaceutically acceptable inorganic or organic acids; for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid; amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; or the like.
Vehicles which can be used in the preparation of pharmaceutical compositions containing the compound of the general formula (I) as the active ingredient may include a sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler, perfume or the like; such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla aroma or the like.
Daily dosage of the compound of the general formula (I) may be varied depending on age, sex of a patient, degree of disease, etc. and generally 1.0 mg to 5,000 mg per day may be administered one to several times.
The compounds of the general formula (I) according to the present invention wherein xe2x80x94Nxe2x95x90Cxe2x80x94 forms a single bond and xe2x80x94Cxe2x95x90Yxe2x80x94 forms a double bond, may be prepared by the following scheme I. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, Y and Z are as defined above, and Lie is a conventional leaving group such as halogen, sulfonyl or the like.
The above process comprises reacting a compound of the general formula (2) with a xe2x80x94C(xe2x95x90Y)xe2x80x94 group-providing agent in an organic solvent to obtain a compound of the general formula (3) and successively reacting the compound of the formula (3) with a compound of the general formula (4) to give the compound of the general formula (5). Then, the compound of the formula (5) may be reacted with an alkylating agent or an arylating agent in the presence of a base to give a compound of the general formula (Ia).
The xe2x80x94C(xe2x95x90Y)xe2x80x94 group-providing agent used in the above reaction may include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide and phenylchloroformate, and it may be used in an amount of 1-1.5 equivalent, preferably 1-1.1 equivalent to the starting compound.
organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.
And also the reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base. Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
The reaction may be carried out at a temperature between 3xc2x0 C. and boiling point of the solvent used, preferably at 50xc2x0 C.-100xc2x0 C. and for 5-48 hours, preferably for 10-24 hours.
The reaction of the compound (3) with the compound (4) to give the compound (5) may be carried out in the presence of a conventional organic solvent at the temperature of 50-100xc2x0 C. for 5-48 hours. The compound (4) may be used by 1-1.5 equivalent.
And also the reaction is preferably carried out in the presence of a conventional inorganic or organic base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.
Then, the compound of the formula (5) may be reacted with an alkylating agent or an arylating agent in the presence of a conventional organic or inorganic base to give a compound of the general formula (Ia).
The alkylating agent and arylating agent used in the above step may include C1-C8 alkylhalide, C1-C8 alkylsulfonate, substituted or unsubstituted C3-C8 cycloalkyl halide, arylhalide, and substituted or unsubstituted C3-C8 cycloalkyl sulfonate.
C1-C8 alkyl halide means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, propyl bromide, propyl iodide, butyl chloride, butyl bromide, butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, bromo ehtylacetate or the like.
C1-C8 alkylsulfonate means methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate or the like.
Substituted or unsubstituted C3-C8 cycloalkyl halides mean cyclopropyl chloride, cyclopropyl bromide, cyclopropyl iodide, cyclobutyl chloride, cyclobutyl bromide, cyclobutyl iodide, cyclopentyl chloride, cyclopentyl bromide, cyclopentyl iodide, cyclohexyl chloride, cyclohexyl bromide, cyclohexyl iodide, cyclopropyl methyl chloride, cyclopropyl methyl bromide, cyclopropyl methyl iodide, cyclobutyl methyl chloride, cyclobutyl methyl bromide, cyclobutyl methyl iodide, cyclopentyl methyl chloride, cyclopentyl methyl bromide, cyclopentyl methyl iodide, cyclohexyl methyl chloride, cyclohexyl methyl bromide, cyclohexyl methyl iodide, or the like.
Aryl halides may include benzyl chloride, benzyl bromide, benzyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, toluyl chloride, toluyl bromide and toluyl iodide.
Substituted or unsubstituted C3-C8 cycloalkyl sulfonate may include cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, cyclopropyl methyl sulfonate, cyclobutyl methyl sulfonate, cyclopentyl methyl sulfonate and cyclohexyl methyl sulfonate.
Aryl sulfonate may include benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, or the like.
The reaction may be carried out in a conventional organic solvent as such as, for example, tetrahydrofuran, dichloromethane, chloroform, dimethyl sulfoxide, acetonitrile and dimethylformamide.
The conventional inorganic or organic base used in above step may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
In the above reaction process, if any acid material is formed, a basic material may be added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be alkali metal hydroxide, alkali earth metal hydroxide, alkali metal oxide, alkali earth metal oxide, alkali metal carbonate, alkali earth metal carbonate, alkali metal hydrogen carbonate, alkali earth metal hydrogen carbonate such as for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, calcium bicarbonate or the like, and organic amines.
The compounds of the general formula (2) and the formula (4) are known compounds, or may be prepared by a known method described in, for example, Farmaco(pavia) Ed, Sci., 18(8), 557-65(1963) or by a similar method thereto.
A compound of the general formula (I) wherein xe2x80x94Cxe2x95x90Yxe2x80x94 forms a single bond and xe2x80x94Nxe2x95x90Cxe2x80x94 forms a double bond may be prepared by the following scheme II 
wherein R1, R2, R3, R4, R5, R6, R7, X1, X2, Y and Z are as defined above, and Rxe2x80x2 is lower alkyl such as methyl and ethyl.
A compound of the general formula (II), which may be prepared by a known method, is reacted with an alkylating agent in the presence of a base to give a compound of the general formula (Ixe2x80x2). Then, the compound of the formula (Ixe2x80x2) is reacted with a substituted or unsubstitued amine in the presence of a base to give a compound of the general formula (Ib).
The reaction may be carried out at a temperature between 3xc2x0 C. and boiling point of the solvent used, preferably at 50xc2x0 C.-100xc2x0 C. for 5-48 hours, preferably for 10-24 hours.
The alkylating agent may be used in an amount of 1-1.5 equivalent to the compound (II). The alkylating agent may include C1-C8 alkyl halide, C1-C8 alkylsulfonate, substituted or unsubstituted C3-C8 cycloalkyl halide, aryl halide and substituted or unsubstituted C3-C8 cycloalkyl sulfonate.
The reaction may be carried out in a conventional organic solvent as described above.
The conventional inorganic or organic base as described above may be used in the above process.
The compound of the formula (Ixe2x80x2) is reacted with a substituted or unsubstitued amine in the presence of a conventional base to give a compound of the general formula (Ib).
The reaction also may be preferably carried out in a conventional organic solvent as described above.
The conventional inorganic or organic base described above may be used in the above reaction step.
In the above reactions, if any acid material is formed, any basic material may be preferably added as a scavenger in order to eliminate the acid material from the reaction phase. Such basic material may be the organic or inorganic bases as described in the scheme I above.
The compound of the general formula (II) is a known compound, or may be prepared by a known method described in, for example, U.S. Pat. No. 5,780,472, PCT/KR97/00128 or by a similar method thereto.
Hereinafter the present invention will be described in more details with reference to following examples but it is not intended to limit the scope of the invention thereinto.
Compounds of the general formula (Ia) were prepared in following examples according to the above-mentioned process. 
wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, Y and Z are as defined above.
The compounds of the general formula (Ib) were prepared in the following examples according to the above-described process. 
wherein, R1, R2, R3, R4, R5, R6, R7, X, Y and Z are as defined above.